One unique feature of SPECT is the ability to use two pharmaceuticals labeled with different isotopes emiting photons with different energies to make simultaneous measurements of different physiological processes. Simultaneous acquisition of projection data from two isotopes has the advantage that it allows measurement of two potentially related processes (e.g., rest and stress perfusion and receptor density) at the same time. This may add additional diagnostic information and, in addition, there are practical advantages such as increased patient throughput, elimination of problems with registration and results in common patient motion in the two studies. However, due to scatter in the patient and gamma camera and the poor energy resolution of conventional gamma cameras, dual isotope acquisition will result in crosstalk contamination of the two sets of projection data. In this work we hypothesize that we can develop methods for simultaneously acquiring and reconstructing dual isotope images that can reduce the effects of this crosstalk to the point where the images have diagnostic image quality close to that which they would have if acquired separately. We have chosen to focus on two specific applications: dual isotope Tc-99m/T1-201 stress/rest myocardial perfusion SPECT and dual isotope Tc-99m/l-123 brain SPECT. Toward this end we propose to: (1) Develop improved acquisition methods for Tc-99m/T1-201 and Tc-99m/I-123 imaging including optimal energy windows and relative activities: (2) develop iterative reconstruction based compensation methods to compensate for the cross-talk including accurate models for the cross- talk producing effects: (3) to evaluate these methods using phantom and simulation experiments combined with quantitative measures of image quality, mathematical observers and human observer studies: and (4) to perform a clinical evaluation of simultaneous and separate acquisition of dual isotope rest/stress myocardial perfusion imaging. At the end of the proposed funding period we believe that we will have developed and evaluated practical methods that can be applied to the clinically important application of rest/stress myocardial perfusion SPECT. Given the frequency with which this procedure is performed and the significant improvement in both patient comfort and clinical throughput, we believe this would have a substantial impact on clinical practice. We also will have developed techniques for simultaneous Tc-99m/I-123 brain imaging that may prove important as new I-123 and Tc-99m labeled brain agents are developed and marketed.